The VEGF-A inhibitor sFLT-1 improves renal function by reducing endothelial activation and inflammation in a mouse model of type 1 diabetes

Abstract

Aims/hypothesisAnimal models of diabetic nephropathy show increased levels of glomerular vascular endothelial growth factor (VEGF)-A, and several studies have shown that inhibiting VEGF-A in animal models of diabetes can prevent albuminuria and glomerular hypertrophy. However, in those studies, treatment was initiated before the onset of kidney damage. Therefore, the aim of this study was to investigate whether transfecting mice with the VEGF-A inhibitor sFlt-1 (encoding soluble fms-related tyrosine kinase 1) can reverse pre-existing kidney damage in a mouse model of type 1 diabetes. In addition, we investigated whether transfection with sFlt-1 can reduce endothelial activation and inflammation in these mice.MethodsSubgroups of untreated 8-week-old female C57BL/6J control (n = 5) and diabetic mice (n = 7) were euthanised 5 weeks after the start of the experiment in order to determine the degree of kidney damage prior to treatment with sFLT-1. Diabetes was induced with three i.p. injections of streptozotocin (75 mg/kg) administered at 2 day intervals. Diabetic nephropathy was then investigated in diabetic mice transfected with sFlt-1 (n = 6); non-diabetic, non-transfected control mice (n = 5); non-diabetic control mice transfected with sFlt-1(n = 10); and non-transfected diabetic mice (n = 6). These mice were euthanised at the end of week 15. Transfection with sFlt-1 was performed in week 6.ResultsWe found that transfection with sFlt-1 significantly reduced kidney damage by normalising albuminuria, glomerular hypertrophy and mesangial matrix content (i.e. glomerular collagen type IV protein levels) (p < 0.001). We also found that transfection with sFlt-1 reduced endothelial activation (p < 0.001), glomerular macrophage infiltration (p < 0.001) and glomerular TNF-α protein levels (p < 0.001). Finally, sFLT-1 decreased VEGF-A-induced endothelial activation in vitro (p < 0.001).Conclusions/interpretationThese results suggest that sFLT-1 might be beneficial in treating diabetic nephropathy by inhibiting VEGF-A, thereby reducing endothelial activation and glomerular inflammation, and ultimately reversing kidney damage.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-017-4322-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Chemerin/ChemR23 axis promotes inflammation of glomerular endothelial cells in diabetic nephropathy

“…31 HG was showed to induce renal glomerular endothelial hyperpermeability by damaging the tight junction between cells. Growing evidence indicates that dysfunction of GEnCs could aggravate renal injury in DN.…”

“…In the DN mice model, inhibiting VEGF-A could reduce endothelial activation and glomerular inflammation, therefore ultimately reversing kidney damage. 31 HG was showed to induce renal glomerular endothelial hyperpermeability by damaging the tight junction between cells. 32 In our study, we cultured GEnCs and then stimulated them with HG or chemerin.…”

Role of VEGF-A and LRG1 in Abnormal Angiogenesis Associated With Diabetic Nephropathy

“…VEGF-A inhibitor sFlt-1 (soluble fms-related tyrosine kinase 1) is observed to reverse renal impairment by decreasing albuminuria, glomerular hypertrophy, and mesangial matrix expansion in mice diabetic mice. In addition, as reflected by decreased levels of vascular cell adhesion molecule 1 (VCAM-1), it also reduced VEGF-A-induced endothelial activation ( Bus et al, 2017 ).…”

COMP-angiopoietin-1 mitigates changes in lipid droplet size, macrophage infiltration of adipose tissue and renal inflammation in streptozotocin-induced diabetic mice

“…It has been demonstrated that high glucose levels can increase proinflammatory molecules such as intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in endothelial cells [ 14 ]. Recently, vascular endothelial growth factor-A inhibitor ameliorated renal inflammation in a mouse model of type 1 diabetes [ 15 ]. Thus, down-regulation of renal endothelial activation, especially in the early stage, may have a protective role against diabetic nephropathy.…”